WO2008093960A1 - Nouveaux inhibiteurs de la dipeptidyl peptidase iv - Google Patents

Nouveaux inhibiteurs de la dipeptidyl peptidase iv Download PDF

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WO2008093960A1
WO2008093960A1 PCT/KR2008/000428 KR2008000428W WO2008093960A1 WO 2008093960 A1 WO2008093960 A1 WO 2008093960A1 KR 2008000428 W KR2008000428 W KR 2008000428W WO 2008093960 A1 WO2008093960 A1 WO 2008093960A1
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substituted
unsubstituted
alkyl
preparation
mmol
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PCT/KR2008/000428
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Ki Dong Koo
Hyejin Jung
Chang-Seok Lee
In Sang Lee
Dong Jun Yeo
Oh Hwan Kwon
Kyoung-Hee Kim
Dongchul Lim
Youn Hoa Kim
Minsun Chang
Ji Young Kim
Jong Sung Koh
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Lg Life Sciences, Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of novel structure, having good inhibition activity versus Dipeptidyl Peptidase-IV (DPP-IV), methods of preparing the same and pharmaceutical compositions containing the same as an active agent.
  • DPP-IV Dipeptidyl Peptidase-IV
  • Diabetes mellitus has serious effects on people's health and accompanies various complications.
  • type I diabetes mellitus characterized by little or no insulin secretory capacity due to the destruction of pancreatic cells
  • type II diabetes mellitus characterized by insulin deficiency and insulin resistance due to other causes.
  • the prevalence of type II diabetes mellitus is 90% or more of total patients with diabetes mellitus.
  • Representative examples of complications accompanying diabetes include hyperlipidemia, hypertension, retinopathy and renal insufficiency (Paul Zimmer, et al., Nature, 2001, 414, 782).
  • Sulfonylureas (stimulating insulin secretion in pancreatic cells), biguanides (inhibiting glucose production in the liver), ⁇ -glucosidase inhibitors (inhibiting glucose absorption in the intestines), etc. have been used as agents to treat diabetes.
  • peroxisome pro- liferator- activated receptor gamma (PP AR ⁇ ) accelerators Thiazolidinediones, increasing insulin sensitivity
  • these drugs have side effects such as hypoglycemia, weight gain and the like (David E. Moller, Nature, 2001, 414, 821). Accordingly, there is a strong need to develope diabetes therapeutic agents with decreased side effects, in particular without inducing hypoglycemia and weight gain.
  • DPP-IV dipeptidyl peptidase-IV
  • GLP-I glucagon-like protein 1
  • pancreatic ⁇ -cells pancreatic ⁇ -cells in vivo and plays an important role in the production and secretion of insulin.
  • GLP- 1 is inactivated by DPP-IV, and DPP-IV inhibitors have been reported to increase insulin secretion by means of inhibiting said inactivation mechanism.
  • DPP-IV inhibitors are also being developed as agents for treatment of obesity because they lead to satiety in rats and slow down digestion of foods in the intestines, resulting in weight loss. Further, many investigators have also shown that DPP-IV inhibitors control blood glucose and lipid levels in animal experiments (Pospislik J. A., et al, Diabetes, (2002) 51, 943-950). In this regard, DPP-IV inhibitors can be considered as potentially useful agents for treatement of diabetes.
  • DPP-IV inhibitors [4] To date, many candidate materials as DPP-IV inhibitors have been on clinical trials, and Sitagliptin of Merck Company had gained FDA acceptance. Much research for developing DPP-IV inhibotors has focused on materials in which cyano group is bonded to pyrrolidine ring. Representative examples of these DPP-IV inhibitors, series of cy- anopyrrolidine, are WO00/34241, WO04/064778, WO03/004498 and WO03/082817. Other examples of DPP-IV inhibitors, series of xanthine not distributed with peptide bond, are WO02/062764, WO03/068757 and WO04/087053.
  • DPP-IV inhibitors using ⁇ -amino acid derivatives have been recently reported including WO03/004498.
  • WO03/082817, WO05/120494, WO05/120494 and WO 05/056003 have also been reported.
  • These DPP-IV inhibitors set forth in the above documents are based upon cyclic compounds having rings connected with amide bond, which is similar to that of the present invention; however, the molecular structures substituted with phenyl groups, which are represented as Ar or Z in the above documents, are entirely different from the structures substituted with saturated or unsaturated, 5-membered or 6-membered cyclic moiety in the present invention.
  • DPP-IV inhibitors according to the present invention having the molecular structure in which a lactam ring is substituted at the phenyl group position, and the method for perparation thereof have not been disclosed in the prior art.
  • n 0, 1 or 2;
  • a 1 , A 2 and A 3 are each independently selected from the group consisting of
  • R' is linear or branched Ci-C 7 alkyl
  • R' and R" are each independently hydrogen, or linear or branched Ci-C 7 alkyl
  • R' is linear or branched Ci-C 7 alkyl
  • R' and R" are each independently hydrogen, linear or branched Ci-C 7 alkyl, or substituted or unsubstituted phenyl; [28] (9) substituted or unsubstituted phenyl,
  • group(s) for substitution is/are each independently one or more selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, OH, CN, COOH and
  • group(s) for substitution is/are each independently one or more selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, OH, CN, COOH and
  • m is 1 or 2
  • X is -NH-, -O- , -S-, -CONR- or -CO-
  • Y is each independently hydrogen, -SO 2 -R, -CH 2 -R, -CO-R, -CONH-R, substituted or unsubstituted het- erocycle, or halogen-substituted or unsubstituted phenyl
  • R is each independently hydrogen, substituted or unsubstituted Ci-Ci 0 alkyl, or halogen-substituted or unsubstituted phenyl;
  • D) B is selected from the Formula (II) or Formula (III) groups below:
  • n 0, 1 or 2;
  • D is selected from the group consisting of sulfur(S), oxygen (O), NR' and CRR';
  • R and R' are each independently selected from hydrogen or linear or branched Ci-C 7 alkyl
  • R 1 , R 2 , R 3 , R 4 and R 5 are selected from the group consisting of,
  • R' is linear or branched Ci-C 7 alkyl
  • R' and R" are each independently hydrogen, or linear or branched Ci-C 7 alkyl
  • R' is linear or branched Ci-C 7 alkyl
  • R' and R" are each independently hydrogen, or linear or branched Ci-C 7 alkyl
  • group(s) for substitution is/are one or more than two each independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, OH, CN, COOH and NH 2 ;
  • group(s) for substitution is/are each independently one or more selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, OH, CN, COOH and NH 2 ;
  • group(s) for substitution is/are each independently one or more selected from the group consisting of halogen, OR', NR'R", substituted or unsubstituted linear or branched Ci-Ci 0 alkyl, CN, COOR', CONR'R", substituted or unsubstituted phenyl, substituted or unsubstituted C 3 -C 6 cycloalky, or substituted or unsubstituted heterocycle, where R' and R" are each independently hydrogen or linear or branched Ci-C 7 alkyl.
  • Ai, A 2 and A 3 may be each independently hydrogen, halogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted heterocycle, CONR'R" or -CH 2 -X-Y, where R' and R" are each independently hydrogen, linear or branched Ci-C 7 alkyl, or substituted or unsubstituted phenyl; X is - NH-, -O-, -S-, or -CO-; and Y is substituted or unsubstituted phenyl, -SO 2 -R, -CO-R, - CONH-R, or substituted or unsubstituted heterocycle, wherein R is substituted or unsubstituted Ci-Cio alkyl or phenyl, and the phenyl is preferably halogen-substituted or unsubstituted phenyl
  • Z is -CH 2 -, Ai, A 2 and A 3 are each independently hydrogen, halogen, C 3 -C 6 cycloalkyl-substituted or unsubstituted heterocycle, or -CH 2 - X-Y, wherein X is -NH-, or -O-; and Y is each independently -SO 2 -R, -CO-R, or halogen-substituted or unsubstituted phenyl, wherein R is substituted or unsubstituted Ci-Cio alkyl, or halogen-substituted or unsubstituted phenyl.
  • R is preferably halogen-substituted or unsubstituted phenyl.
  • a 2 and A 3 may be interconnected to form a cyclic structure (E), E may be selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted heterocycle, and substituted or unsubstituted C 3 -C 6 cycloalkyl.
  • E is preferably phenyl.
  • group(s) for substitution may be each independently substituted or unsubstituted linear or branched Ci-C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heterocycle, and the heterocycle is one selected from the group consisting of furan, thiophene, pyrrol, pyrrolidine, imidazole, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolidine, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, im- idazolidine, pyrazolidine, oxazolidine, isoxazolidine, thia
  • Ri, R 2 , R 3 , R 4 and R 5 are preferably, each independently, hydrogen, halogen, or substituted or unsubstituted linear or branched Ci-Ci 0 alkyl.
  • the compound of formula (I) is a compound as represented by Formula (Ia) or pharmaceutically acceptable salt below:
  • n is 0 or l
  • a 4 and A 5 are each independently selected from the following groups,
  • R' is linear or branched Ci-C 7 alkyl
  • R' and R" are each independently hydrogen or linear or branched Ci-C 7 alkyl; [80] (5) substituted or unsubstituted linear or branched Ci-C 7 alkyl
  • R' is linear or branched Ci-C 7 alkyl
  • R' and R" are each independently hydrogen or linear or branched Ci-C 7 alkyl
  • group(s) for substitution is/are each independently one or more selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, CN, OH, COOH and
  • group(s) for substitution is/are each independently one or more selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, CN, OH, COOH and
  • the compound according to the present invention may be a compound as represented by Formula (Ib) below wherein Z is -CH 2 -, and the compound can also include isomers thereof.
  • preferable is the compound in which the carbon substituted with an amine group (-NH 2 ) forms a stereo center, as seen in the structure of Formula (Ib) below.
  • the compound according to the present invention may be a compound as represented by Formula (Ic) below wherein Z is -CO-, and the compound can also include isomers thereof.
  • Z is -CO-
  • preferable is the compound in which the carbon substituted with an amine group (-NH 2 ) forms a stereo center, as seen in the structure of Formula (Ic) below.
  • Formula (Ic) can be diastereomers.
  • the compounds of Formula 1 according to the present invention are compounds as defined below, but are not limited to the following compounds: [101] l-[(2S)-2-amino-4- ⁇ (2S)-2-[(3-fluorophenoxy)methyl]pyrrolidine-l-yl ⁇ butyl]-5,5-dif luoropiperidine-2-one [102] N-( ⁇ (2S)-l-[(3S)-3-amino-4-(5,5-difluoro-2-oxopiperidine-l-yl)butyl]pyrrolidine-2-y l ⁇ methyl)me thane sulfonamide [103] l- ⁇ (2S)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6
  • the compound of the present invention may form an acid adduct with a pharmaceutically acceptable acid.
  • the term "pharmaceutically acceptable salt” includes inorganic salts, organic salts, amino acid salts, etc., and more specifically, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; salts with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid and the like; salts with methanesulfonic acid, p-toluenesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
  • organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fum
  • the compound of the present invention or the pharmaceutically acceptable salts thereof can be present in a form of hydrate or solvate.
  • the present invention is also directed to processes for preparation of the compound of Formula (I), and the compound of Formula (I) wherein Z is -CH 2 - can be prepared from the following important intermediates.
  • One of the intermediates is an amino acid derivative represented by the following compound of Formula (IV), and the other is a cycloamine or its corresponding salt (representatively, hydrochloric acid salt or trifluoroacetic acid salt) represented by the following Formula (V).
  • the compound of Formula (I) wherein Z is -CO- can be prepared from an amino acid derivative represented by the compound of Formula (IV) below and a cycloamine or its corresponding salt represented by the following Formula (V).
  • n, A 1 , A 2 , A 3 and B are as defined in the above;
  • Pi is an amine-protecting group such as t-butoxycarbonyl (Boc), benzyl oxycarbonyl
  • Pi is as defined in the above;
  • P 2 is a linear or branched Ci-C 7 alkyl, preferably t-butyl or isopropyl.
  • Intermediates (1) and (V) being aspartic acid derivatives are commercially obtainable starting materials.
  • the intermediates (1) and (V) are firstly reacted with isobutylchlo- roformate and N-methylmorpholine in the presence of anhydrous tetrahydrofuran (THF), followed by being reduced with sodiumborohydride (NaBH 4 ) to prepare intermediates (2) and (2') are prepared.
  • THF anhydrous tetrahydrofuran
  • NaBH 4 sodiumborohydride
  • the intermediate (2) is oxidized to give the aldehyde intermediates (3) and (3') by Swern oxidation method using dimethylsul- furoxide (DMSO) and oxalic acid in the presence of methylenechloride solvent or by using 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO), lithium bromide and sodiumbicarbonate.
  • Cycloamides (4) and (4') can be prepared from the aldehyde intermediates (3) and (3') by using an amine 'T-NH 2 ' or its corresponding salt (for examples, hydrochloric acid salt or trifluoroacetic acid salt) and sodiumtriacetoxy- borohydride (NaBH(OAc) 3 ).
  • Amine'T-NH 2 ' or its corresponding salt as a start material for synthesizing the intermediate (4) in Reaction Scheme 1 and 1-1 can be represented by Fomula (Ha) and Fomula (Ilia).
  • the compounds of the following Fomula (Ha) and Fomula (Ilia) are important intermediates for preparing the compounds of the Fomula (II) and Fomula (III).
  • Intermediate (5) can be commercially obtainable, or prepared by introducing amine- protecting group (P 1 ) from an amine which is commercially obtainable, in which the amine-protecting group (P 1 ) generally means t-butoxycarbonyl group (Boc).
  • the intermediate (5) is first reacted with an amine base (for examples, triethylamine or N,N'-diisopropylethylamine) and isobutylchloroformate, followed by preparing a thiazoketone intermediate using diazomethane, and silverbenzoate and amine base are added thereto in the presence of methanol solvent, then the amino acid intermediate (5a) is obtained by sonication method. 4N hydrochloric acid-dioxane solution or tri- fluoroacetic acid is added to the thus prepared intermediate (5a) to give the compound of Fomula (Ha).
  • an amine base for examples, triethylamine or N,N'-diisopropylethylamine
  • isobutylchloroformate followed by preparing a thiazoketone intermediate using diazomethane, and silverbenzoate and amine base are added thereto in the presence of methanol solvent, then the amino acid intermediate (5a) is obtained by
  • the intermediate (IV) can be prepared by the following Reaction Scheme 3 using a commercially obtainable intermediate (IV).
  • the compound of Fomula (IV) can be prepared by reacting isobutylchloroformate and N- methylmorpholine in the presence of tetrahydrofuran (THF), and then reducing the resulting compound with sodiumborohydride (NaBH 4 ), in the same reduction manner as in the starting material (1) in Reaction Scheme 1.
  • An amine or its corresponding salt as another important intermediate represented by the following Fomula (V) may be, for example, the compounds of Fomulas (Va), (Vb) and (Vc) below.
  • Intermediate (6) can be commercially obtainable, or prepared by introducing an amine-protecting group (Pi) from a commercially obtainable amine, in which the amine-protecting group (Pi) generally means t-butoxycarbonyl group (Boc).
  • Intermediate (7) can be prepared from the intermediate (6) with triphenylphosphine (TPP), diphenylphosphorylazaide (DPPA) and diethylazodicarboxylate (DEAD) in anhydrous tetrahydrofuran (THF) as solvent.
  • TPP triphenylphosphine
  • DPPA diphenylphosphorylazaide
  • DEAD diethylazodicarboxylate
  • THF anhydrous tetrahydrofuran
  • the intermediate (7) is converted to amine intermediate (8) by palladium-activated carbon in alcohol as solvent, and the amine intermediate (8) thus obtained is reacted with an acid derivative or amine receptor to give intermediate (9).
  • the reactant is reacted under the same condition as the condition using EDC, HOBT and amine base, as described in the above.
  • Intermediate (Vb) is obtained by removing an amine- protecting group (P) from the intermediate (9) obtained by polymerization.
  • amine-protecting group (P) is t-butoxycarbonyl (Boc)
  • the amine-protecting group (P) is removed by 4N hydrochloric acid-dioxane solution or trifluoroacetic acid (TFA).
  • Amine or its corresponding salt represented by Fomula (V) may be the compounds of the following Fomulas (Vd), (Ve) and (Vf), where Ai in Formula (I) is oxadiazole or oxazolidine as heterocycle.
  • intermediate (11) is reacted with carbodiimidazole and alkyl- amidoxim (12) to give intermediate (13).
  • An amine-protecting group (P) of the intermediate (13) thus obtained is removed to give intermediate (Vd).
  • the amine- protecting group is t-butoxycarbonyl group (B oc)
  • amine-protecting group is removed by 4N hydrochloric acid-dioxane solution or trifluoroacetic acid.
  • intermediate (14) is reacted with acid derivative (15) and N,N-dimethylformamide (DMF) in the same condition as in Reaction Scheme 5 to give intermediate (16), and an amine-protecting group (P) of the intermediate (16) is removed to give intermediate (Ve).
  • the amine-protecting group is removed by 4N hydrochloric acid-dioxane solution or trifluoroacetic acid in which the amine-protecting group is t-butoxycarbonyl (B oc).
  • intermediate (11) and amino alcohol starting material (17) are used to give intermediate (18) by EDC coupling reaction.
  • Intermediate (19) is prepared from the intermediate (18) using diethylaminosulfur trifluoride (DAST).
  • DAST diethylaminosulfur trifluoride
  • An amine- protecting group of the intermediate (19) is removed to give intermediate (Vf).
  • the amine-protecting group is t-butoxycarbonyl (B oc)
  • the amine-protecting group (P) is removed by 4N hydrochloric acid-dioxane solution or trifluoroacetic acid.
  • a 4 , A 5 and n are as defined in the above above, and an amine- protecting group (P) is t-butoxycarbonyl (Boc), benzyl (Bn), benzylbenzyloxycarbonyl and the like, preferably t-butoxycarbonyl (Boc).
  • Dicarbonyl intermediate (20) is reacted with amidine (21) to form heterocycle, i.e., intermediate (22) in the presence of pyridine solvent.
  • amine-protecting group (P) is t-butoxycarbonyl group (Boc)
  • an amine-protecting group (P) is removed by 4N hydrochloric acid-dioxane solution or trifluoroacetic acid to give amine or its corresponding salt (Vg).
  • the detailed preparation method is also described in Korean Patent Application No. 2006-29138.
  • an aldehyde intermediate (23) is obtained by oxidation using 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO), lithium bromide, sodi- umbicarbonate, and alcohol (IV) as a starting material obtained from Reaction Scheme 3, or by Swern oxidation method using dimethylsulfuroxide (DMSO) and oxalic acid in the presence of methylenechloride solvent.
  • Intermediate (24) can be obtained by reducing aminization reaction of the aldehyde intermediate (23) and the compound of Fomula (V).
  • an amine-protecting group of the intermediate (24) is removed by 4N hydrochloric acid- dioxane solution or trifluoroacetic acid/methylene chloride to give Compound (I) in which the substituent Z is CH 2 .
  • the compound of Fomula (I) in which the substituent Z is -CO- can be converted to Compound (I 1 ), by the following Reaction Scheme 10, which can is prepared from the compounds of Fomula (V) and Fomula (IV) obtained by the above method.
  • Intermediate (25) can be prepared by a general amino acid synthesis method; for example, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBT) and amine base (for example, N,N-diisopropylethylamine) are reacted in the presence of N,N-dimethylformamide (DMF) or ethylene chloride solution.
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • HOBT 1-hydroxybenzotriazole
  • amine base for example, N,N-diisopropylethylamine
  • Compound (T) in which the substituent Z is -CO- can be obtained from the intermediate (25) by treatment with 4N hydrochloric acid-dioxane solution or trifluoroacetic acid/methylene chloride in the presence of methylenechloride solvent.
  • a compound of Formula (I) can be isolated and purified from the reaction product by means of conventional methods such as recrystallization, ion electrophoresis, silica gel column chromatography or ion exchange resin chromatography and the like.
  • the present invention also provides a pharmaceutical composition for inhibiting
  • DPP-IV comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • composition can include a mixture of a compound of the invention with other chemical components, such as diluents or carriers. Accordingly, carriers, diluents, excipient(s), or their combination can be included in the pharmaceutical composition, if necessary.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but are not limited to oral, injection, aerosol, parenteral, and topical administrations.
  • the compound of the present invention can be administered in various pharmaceutical dosage forms in accordance with intended use.
  • an active agent more specifically the compound of Formula (I) may be mixed with one or more pharmaceutically acceptable carriers which can be selected depending on the dosage form to be prepared.
  • the pharmaceutical composition according to the present invention can be formulated into dosage forms suitable for injection or oral administration.
  • the compound of Formula (I) may be formulated in a conventional manner using known pharmaceutically acceptable carriers and excipients and presented in unit dosage form or in multidose containers.
  • the formulations may take such forms as solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional dispersing, suspending or stabilizing agents.
  • the active ingredient may be in the powder form for reconstitution with sterile pyrogen-free water, before use.
  • the compound of Formula (I) may also be formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid dosage forms for oral administration include capsule, tablet, pill, powder and granule. Preferable dosage forms are capsule and tablet.
  • the solid dosage forms for oral administration may be obtained by mixing the compound of Formula (I) as an active agent with inactive diluents such as sucrose, lactose, starch and the like and carriers such as lubricant, for example magnesium stearate, including disintegrator, binder and the like.
  • inactive diluents such as sucrose, lactose, starch and the like
  • carriers such as lubricant, for example magnesium stearate, including disintegrator, binder and the like.
  • the compound of Formula (I) and compositions comprising the same according to the present invention may be administrated in combination with other pharmaceutical agents, for example, other diabetes treating agents.
  • the compound of Formula (I) as an active agent can be preferably contained in an amount of about 0.1 ⁇ 1,500 mg unit dosage.
  • the dosage amount of the compound of Formula (I) will be dependent on the subject's weight and age, the nature and severity of the affliction and the judgment of the prescribing physician.
  • the dosage amount required will be about in the range of 1 to 500 mg a day depending on the frequency and strength of the dosage.
  • a total dosage amount of about 5 ⁇ 300 mg a day will be sufficient. In some patients, the dosage amount in a day will be higher than that.
  • the present invention provides the method for treatment or prevention of diseases involving inappropriate activity of DPP-IV by using the compound of Formula (I) as defined in claim 1 in effective dose.
  • diseases caused by inappropriate levels of DPP-IV include, but are in no way limited to, diabetes mellitus, obesity and the like as described above.
  • the present invention isuseful to treat and prevent type II diabetes mellitus. Best Mode for Carrying Out the Invention
  • T-butyl (3S)-3-(hydroxyketyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate obtained in PREPARATION 4(1) was dissolved in 40 mL of anhydrous tetrahydrofuran (THF), and cooled to O 0 C. 3.05 g (116 mmol) of triphenylphosphine was added thereto. To this solution were added dropwise in sequence 2.5 mL (11.6 mmol) of diphenylphos- phorylazide and 1.83 mL (11.6 mmol) of diethylazodicarboxylate (DEAD).
  • THF anhydrous tetrahydrofuran
  • PREPARATION 7 Synthesis of t- butyll ( 1 S V 3-hydroxy- 1 - r(4-methyl-2-oxo-2.5-dihydro- lH-pyrrole- 1 -yPmethyllpropyl ) carbamate
  • TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy preradical
  • (2S)-l-(3-fluorophenoxy)-N-methylpentane-2-amine chloric acid salt obtained by referring to WO05/ 120494, was added to filterated solution, obtained by drying over anhydrous magnesium sulfate and filtering the methylene chloride layer at room temperature. After 5 minutes, 60 mg (0.285 mmol) of sodium triacetoxyborohydride was added therero. After stirring the suspension solution for 18 hours, the organic layer was separated by extracting with ethylacetate, dried over anhydrous magnesiunsulfate, and then concentrated under reduced pressure. The thus obtained concentrate was isolated and purified with prep-TLC to give 18 mg of the title compound in a yield of 19%.
  • PREPARATION 11 Synthesis of t- butyl( ⁇ SVl-r(5.5-difluoro-2-oxopiperidine-l-vDmethyll-3-r(2SV2-(r(methylsulfonvD amino!
  • PREPARATION 12 Synthesis of t- butyl( ⁇ SV3-r2.4-bis ⁇ rifluoromethylV5.8-dihvdropyridor3.4-dlpyrimidine-7(6HVyll- 1 - IY5.5-difruoro-2-oxopiperidine- 1 -yPmethyllpropyl ) carbamate
  • PREPARATION 13 Synthesis of t- butvK ⁇ SVS-r ⁇ S ⁇ -G-cvclopropyl-l ⁇ -oxadiazole-S-vDpyrrolidine-l-yll-l-rrS.S-di fluoro-2-oxopiperidine- 1 yPmethyllpropyl ) carbamate
  • EXAMPLE 4 Synthesis of l-lflSVl-amino- ⁇ rflSVl-G-cvclopropyl-l.l ⁇ -oxadiazole-S-vD pyrrolidine-l-yll butyl)-5.5-difluoropiperidine2-one [376] o N ⁇
  • PREPARATION 14 Synthesis of t- butyl( ⁇ SVl-r(5.5-difluoro-2-oxopiperidine-lvDmethyll-3-r(2SV2-(r ⁇ henylsulfonvDa minol methyl ⁇ pyrrolidine- 1 -yll propyl ⁇ carbamate
  • PREPARATION 16 Synthesis of t- butyl( ⁇ SVl-3-r(2SV2-G-cvclobutyl-1.2.4-oxadiazole-5-vDpiperidine-l-yll-l-r(5.5-dif luoro-2-oxopiperidine-lyl s )methyllpropyl) carbamate [404] 38 mg of the title compound was obtained in a yield of 32%, in the same manner as in PREPARATION 10, except that 72.2 mg (0.224 mmol) of t- butyl ⁇ (lS)-l-[(5,5-difluoro-2-oxopiperidine-l-yl)methyl]-3-hydroxypropyl ⁇ carbamate obtained in PREPARATION 9 and 57 mg (0.235 mmol) of
  • PREPARATION 17 Synthesis of t- butyl((lS s )-l-[(5.5-difluoro-2-oxopiperidine-l-yl s )methyll-3-[2-(3-furyl s )-4-(trifluorome thyl s )-5.8-dihvdropyrido[3.4-dlpyrimidine-7(6H s )-yllpropyl)carbamate [415] 173 mg of the title compound was obtained in a yield of 58%, in the same manner as in PREPARATION 10, except that 168 mg (0.52 mmol) of t- butyl ⁇ (lS)-l-[(5,5-difluoro-2-oxopiperidine-l-yl)
  • PREPARATION 18 Synthesis of t- butylf ⁇ SV3-rGSV3-r ⁇ ?enzoylamino)metfayl1-34-dihvdroisoquinoline-2flHVyl1-l-r(5
  • PREPARATION 19 Synthesis of t-butylf flSV3-f (2SV2-r ⁇ ?enzoylami no ⁇ methyllpyrrolidine- 1 yl ) - 1 - [(5.5-difluoro-2-oxopiperidine- 1 - vDmethyll propyl ) carba mate
  • 66 mg of the title compound was obtained in a yield of 25%, in the same manner as in PREPARATION 10, except that 168 mg (0.52 mmol) of t- butyl ⁇ (lS)-l-[(5,5-difluoro-2-oxopiperidine-l-yl)methyl]-3-hydroxypropyl ⁇ carbamate obtained in PREPARATION 9 and 138 mg (0.57 mmol) of N-
  • PREPARATION 20 Synthesis of t- butvir ⁇ SV3-r(2S.4SV2-(3-cvclopropyl-1.2.4-oxadiazole-5-ylV4-fluoropyrrolidine-l-v ll-l-(r(4RV4-methyl-2-oxopyrrolidine-l-yllmethyl)propyllcarbamate
  • PREPARATION 21 Synthesis of t- butvir ⁇ SV3-r(2S.4SV2-G-cvclopropyl-1.2.4-oxadiazole-5-ylV4-fluoropyrrolidine-l-v 11-1-1 r(5R)-5-methyl-2-oxopiperidine- 1 -yllmethyl Ipropyllcarbamate
  • PREPARATION 22 Synthesis of t- butyl( ⁇ SV3-r(2S.4SV2-(3-cvclopropyl-1.2.4-oxadiazole-5-ylV4-fluoropyrrolidine-l-v 11-1 - r(4-methyl-2-oxo-2.5-dihydro- lH-pyrrole- 1 -yPmethyllpropyl ) carbamate
  • EXAMPLE 13 Synthesis of l-((2SV2-amino-4-r(2S.4SV2-G-cvclopropyl-1.2.4-oxadiazole-5ylV4- fluoropyrrolidine- 1 -yllbutyl ) -4-methyl- 1.5-dihvdro-2H-pyrrole-2-one
  • (2S,4S)-4-fluoropyrrolidine-l,2-dicarboxylate obtained by referring to WO 03/002553 was dissolved in 16 mL of tetrahydrofuran and 4 mL of distilled water. Thereafter, 250 mg (6.06 mmol) of lithium hydroxide was added thereto, then stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and ethylacetoacetate was added thereto. The resulting solution was neutralized with IN hydrochloric acid, then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 330 mg of the title compound (yield: 70%).
  • (2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazole-5-yl)-4-(l-ethoxyethoxy)pyrrolidine-l-carb oxylate obtained in PREPARATION 24(3) was dissolved in 30 mL of anhydrous ethanol, and then 135 mg (0.536 mmol) of pyridinium p-toluenesulfonate (PPTS) was added thereto. After the solution was heated to 5O 0 C and then cooled to room temperature, the ethanol is removed under reduced pressure to give 1.52 g of the title compound without further purification (yield: 96%).
  • PPTS pyridinium p-toluenesulfonate
  • (2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazole-5-yl)-4-hydroxypyrrolidine-l-carboxylate obtained in PREPARATION 24(4) was dissolved in 10 rnL of anhydrous tetrahy- drofuran (THF), then 34 mg (0.837 mmol) of sodium hydride (55% dispersion in mineral oil) was added thereto in ice bath and stirred for 5 minutes. Thereafter, 0.065 mL (1.05 mmol) of idiomethane as a reaction solution was added thereto, the icebath was removed.
  • THF anhydrous tetrahy- drofuran
  • PREPARATION 26 Synthesis of (2SVN-phenylpiperidine-2-carboxamide hy- drochloric acid salt
  • EXAMPLE 14 Synthesis of l-K2S s )-2-amino-4-[(2S s )-2-(hvdroxymethyl s )pyrrolidine-l-yll-4-oxobutyl)-5.5-difluoro piperidine-2-one
  • PREPARATION 31 Synthesis of t- butvirriS ⁇ -l-rrS.S-difluoro-l-oxopiperidine-l-vDmethyll-S-oxo-S-KlS'l-l-r ⁇ yrimidin e-2-ylthio)methv ⁇ pyrrolidine- 1 -yl Ipropyllcarbamate [588] 41.8 mg of the title compound (yield: 19%) was obtained, in the same manner as in
  • PREPARATION 35 Synthesis of t- butyl(QSV3-r(2SV2-(anilinomethyl s )pyrrolidine-l-yll-l-r(5.5-difluoro-2-oxopiperidine -l-yDmethyll-S-oxopropyDcarbamate
  • EXAMPLE 22 Synthesis of l-((2SV2-amino-4-r(2SV2-(anilinomethyl s )pyrrolidine-l-yll-4-oxobutyl)-5.5-difluorop iperidine-2-one
  • PREPARATION 37 Synthesis of t- butylKlS s )-l-[(5.5-difluoro-2-oxopiperidine-l-yl s )methyll-3-[(3S s )-3-(morpholine-4-ylc arbonvD-S ⁇ -dihvdroisoquinoline-iriH ⁇ -yll-S-oxopropyllcarbamate
  • (3S)-3-(morpholine-4-ylcarbonyl)-l,2,3,4-tetrahydroisoquinoline hydrochloric acid salt obtained by referring to WO 05/056003 and 60.0 mg (0.180 mmol) of (3S)-3-[(t-butoxycarbonyl)amino-4-(5,5-difluoro-2-oxopiperidine-l-yl)butyric acid obtained by referring to Korean Patent Application No. 2006-29138 were used.
  • EXAMPLE 24 Synthesis of l-((2SV2-amino-4-r(3SV3-(morpholine-4-ylcarbonylV3.4-dihvdroisoquinoline-2 ⁇ HV yll -4-oxobutyl ) -5.5-difluoropiperidine-2-one
  • PREPARATION 38 Synthesis of t- butyl( ⁇ SV3-r(2SV2-(3-cvclopropyl-1.2.4-oxadiazole-5-vDpyrrolidine-l-yll-l-r(5.5-di fluoro-2-oxopiperidine- 1 -yPmethyll -3-oxopropyl lcarbamate
  • EXAMPLE 25 Synthesis of l-((2SV2-amino-4-r(2SV2-(3-cvclopropyl-1.2.4-oxadiazole-5-vD pyrrolidine- l-yll-4-oxobutyl)-5.5-difluoropiperidine-2-one
  • PREPARATION 39 Synthesis of t-butyl( ⁇ SV3-r(2SV2-(5-cvclopropyl-1.2.4- ox- adiazole-S-yDpyrrolidine- 1 -yll - 1 - IY5.5-difruoro-2-oxopiperidine- 1 -yPmethyll -3-oxopr opyl) carbamate
  • PREPARATION 40 Synthesis of t- butvir ⁇ SV3-r(2SV2-G-cvclopropyl-1.2.4-oxadiazole-5-vDpyrrolidine-l-yll-l-(r(5RV 5-methyl-2-oxopiperidine- l-yllmethyl)-3- oxopropyllcarbamate
  • PREPARATION 41 Synthesis of t- butyll QSV l-r(5.5-difluoro-2-oxopiperidine- l-vDmethyll-3-oxo-3-r(2SV2-G-phenyl- 1 .2.4-oxadiazole-5-yl)pyrrolidine-l-yllpropyl)carbamate
  • PREPARATION 43 Synthesis of t- butyll (IS)- l-[(5.5-difluoro-2-oxopiperidine- 1-yl) methyll-3-oxo-3-[(2S)-2-(3-pyridine-2-yl-1.2.4-oxadiazole-5-yl)pyrrolidine-l-yll propyl ) carbamate
  • PREPARATION 44 Synthesis of t- butylf flSVl-f rf5RV5-methyl-2-oxopiperidine-l-yl1methyl)-3-oxo-3-r(2SV2-f3-pyridi ne-2-yl- 1.2.4-oxadiazole-5-yl)pyrrolidine- 1 -yllpropyl ) carbamate
  • PREPARATION 2 except that 3.44 g (16.0 mmol) of N-(t-butoxycarbonyl)-L-proline and 1.06 g (8.27 mmol) of N'-hydroxycyclopentanecarboximidamide obtained in PREPARATION 45(1) were used.
  • PREPARATION 46 Synthesis of t- butyl( ⁇ SV3-r(2SV2-(3-cvclopentyl-1.2.4-oxadiazole-5-vDpyrrolidine-l-yll-l-r(5.5-dif luoro-2-oxopiperidine-l-yl s )methyll-3-oxopropyl)carbamate
  • EXAMPLE 32 l-((2SV2-amino-4-r(2SV2-(3-cvclopentyl-1.2.4-oxadiazole-5-vD pyrrolidine- l-yll-4-oxobutyl)-5.5-difluoropiperidine-2- one
  • PREPARATION 50 Synthesis of t- butyl( ⁇ SVl-(r(4RV4-methyl-2-oxopyrrolidine-l-yllmethyl)-3-oxo-3-r(2SV2-G-pyrid ine-2-yl-1.2.4-oxadiazole-5-yl)pyrroridine-l-v ⁇ propyl) carbamate [802] 27.0 mg of the title compound (yield: 55%) was obtained, in the same manner as in
  • PREPARATION 51 Synthesis of t- butyl( ⁇ SV3-r(2SV2-r3-(cvclopropylmethylV1.2.4-oxadiazole-5-yllpyrrolidine-l-yll-l -r(5.5-difluoro-2-oxopiperidine-l-yl s )methyll-3- oxopropyl) carbamate
  • EXAMPLE 37 Synthesis of l-((2SV2-amino-4-r( ' 2SV2-G-cvclobutyl-1.2.4-oxadiazole-5-vDpyrrolidine-l-yll-4-ox obutyl)-5.5-difluoropiperidine-2-one
  • (2S)-2-[(4S)-4-phenyl-4,5-dihydro-l,3-oxazole-2-yl]pyrrolidine-l-carboxylate obtained by referring to WO 05/121131 was dissolved in 4N 1,4-dioxane hydrochloric acid solution (5.0 mL). Thereafter, the resulting solution was stirred for 20 minutes and concentrated under reduced pressure, then the residue was purified with prep-TLC (6:1 CH 2 Cl 2 MeOH) to give 130 mg of the title compound (yield: 82%).
  • PREPARATION 54 Synthesis of t- butvir ⁇ SVl-r(5.5-difluoro-2-oxopiperidine-l-vDmethyll-3-oxo-3-((2SV2-r(4SV4-phe nyl-4.5-dihydro-1.3-oxazole-2-yllpyrrolidine-l-yl)propyllcarbamate
  • PREPARATION 56 Synthesis of t- butvir ⁇ SVl-r(5.5-difluoro-2-oxopiperidine-l-vDmethyll-3-((2S.4SV4-fluoro-2-r(4SV 4-phenyl-4.5-dihydro-1.3-oxazole-2-yllpyrrolidine-l-yl)-3-oxopropyllcarbamate
  • EXAMPLE 39 Synthesis of l-r(2SV2-amino-4-oxo-4-((2S.4SV4-fluoro-2-r(4SV4-phenyl-4.5-dihvdro-1.3-oxazole- 2-yllpyrrolidine-l-yl)-4-oxobutyll-5.5-difluoropiperidine-2-one
  • PREPARATION 58 Synthesis of t- butvir ⁇ SVl-r(5.5-difluoro-2-oxopiperidine-l-vDmethyll-3-((2S.4RV4-hvdroxy-2-r(4 SV4-phenyl-4.5-dihydro-1.3-oxazole-2-yllpyrrolidine-l-yl)-3-oxopropyllcarbamate
  • PREPARATION 59 Synthesis of 4-phenyl-2-r(2SVpyrrolidine-2-yll-1.3-oxazole hy- drochloric acid salt
  • (2S)-2-( ⁇ [(lS)-2-hydroxy- 1-phenylethyl] amino ⁇ carbonyl)pyrrolidine- 1-carboxylate obtained by referring to WO 05/121131 was dissolved in 10 mL of methylenechloride, and 0.65 g (1.54 mmol) of Dess-martin periodinane was added thereto. The resulting solution was stirred for 3 hours, filtered by Cellite and concentrated under reduced pressure. The next step was preceded without further purification.
  • (2S)-2-(4-phenyl-l,3-oxazole-2-yl)pyrrolidine-l-carboxylate obtained in PREPARATION 58(1) was dissolved in 4N 1,4-dioxane hydrochloric acid solution (5.0 ml). The resulting solution was stirred for 20 minutes and concentrated under reduced pressure, and the residue was purified with diethylether to give 140 mg of the title compound (yield: 97%).
  • PREPARATION 60 Synthesis of t- butylf f ISV l-r(5.5-difluoro-2-oxopiperidine- l-yl)methyl1-3-oxo-3-r(2SV2-f4-phenyl- 1 .3-oxazole-2-yl)pyrrolidine-l-yllpropyl)carbamate
  • PREPARATION 62 Synthesis of t- butyl( ⁇ SVl-r(5.5-difluoro-2-oxopiperidine-l-vDmethyll-3-oxo-3-r(2SV2-(5-ri-(triflu oromethyDcyclopropyll - 1.2.4-oxadiazole-3-yl Ipyrrolidine- 1 -yllpropyl ) carbamate
  • EXAMPLE 42 Synthesis of l-((2SV2-amino-4-oxo-4-r(2SV2-(5-ri-(trifluoromethyl s )cvclopropyll-1.2.4-oxadiazol e-3-yl Ipyrrolidine- 1 -yllbutyl ) -5.5-difluoropiperidine-2-one

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Abstract

La présente invention concerne de nouveaux composés présentant une excellente activité inhibitrice vis-à-vis de la dipeptidyl peptidase IV (DPP IV), ainsi que des procédés de préparation de ces composés et des compositions pharmaceutiques contenant lesdits composés comme agent actif.
PCT/KR2008/000428 2007-01-30 2008-01-23 Nouveaux inhibiteurs de la dipeptidyl peptidase iv WO2008093960A1 (fr)

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WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
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WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
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JP2013542245A (ja) * 2010-11-11 2013-11-21 レッドエックス ファーマ リミテッド 薬物誘導体
JP2013543484A (ja) * 2010-09-03 2013-12-05 エルジー・ライフ・サイエンシーズ・リミテッド 医薬品合成用中間体化合物の製造方法
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
EP3565543A4 (fr) * 2017-01-06 2020-10-14 The Regents of The University of California Modulateurs du récepteur opioïde de type mu
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EP2404909A1 (fr) * 2008-12-16 2012-01-11 Tianjin Institute Of Pharmaceutical Research Dérivé de thiazole de type amide, sa méthode de synthèse et ses applications
EP2404909A4 (fr) * 2008-12-16 2012-05-16 Tianjin Inst Pharm Research Dérivé de thiazole de type amide, sa méthode de synthèse et ses applications
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
JP2013543484A (ja) * 2010-09-03 2013-12-05 エルジー・ライフ・サイエンシーズ・リミテッド 医薬品合成用中間体化合物の製造方法
JP2013542245A (ja) * 2010-11-11 2013-11-21 レッドエックス ファーマ リミテッド 薬物誘導体
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
EP3565543A4 (fr) * 2017-01-06 2020-10-14 The Regents of The University of California Modulateurs du récepteur opioïde de type mu
US11352316B2 (en) 2018-04-04 2022-06-07 Epiodyne, Inc. Opioid receptor modulators and products and methods related thereto
US11634396B2 (en) 2021-04-05 2023-04-25 Epiodyne, Inc. Opioid receptor modulators

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